Blood-based prion detection: a breakthrough?

BY YUSHA SUN

Prion diseases are a group of infectious, mostly fatal neurological diseases that affect all animals, including humans. Prion diseases are caused by prions, infectious agents made from a conformationally altered form of the natural PrP protein. They are especially dangerous due to their ability to propagate in the body and brain indefinitely without the requirement of genetic material. One of the most common forms of prion disease, known as the variant Creutzfeldt-Jakob disease (vCJD), or more popularly mad cow disease, results from eating the meat of cattle afflicted with a form of encephalopathy.

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Prions, or misfolded proteins in the brain, cause deadly diseases that have potential to be treated.

What makes this disease particularly elusive, however, is the fact that the infectious form of PrP, known as PrPSc, can only be detected in the nervous system at very late stages of the disease, making early diagnosis particularly difficult. Definitive diagnoses involve post-mortem analysis of nervous tissue or biological fluid analysis at late stages. Therefore, developing a noninvasive method to determine presence of the prion is imperative to allow early diagnosis.

Soto, et al., a research group at the University of Texas Health Science Center in Houston, recently published a paper in Science Translational Medicine proposing a new method that could potentially used for early, noninvasive diagnosis of vCJD. The group utilized a novel amplification technology known as protein misfolding cyclic amplification (PMCA), which takes existing prion units and accelerates the process of the conversion from normal protein to prion. In this way, any tiny amount of prion PrPSc can be amplified and definitively detected, through sonication, a process using sound waves to break down prion clumps and accelerate their infectivity. The goal of using PMCA on vCJD research was to develop the amplification technology that would allow us to detect the prion in blood samples where it exists in very low concentration and to subsequently estimate the quantity of the prion present in the blood.

The group specifically started off by placing tiny amounts of vCJD brain sample into healthy blood, which allowed them to evaluate the limits at which the PMCA technology could detect the prion. In fact, only a tiny amount of blood (0.37 microliters) was needed to detect vCJD after PMCA was applied. They then analyzed the blood samples of 14 patients actually suffering from the disease and compared to blood sampled from healthy individuals and from individuals with other neurodegenerative disorders; the technology was able to detect PrPSc in vCJD patients with 100% sensitivity, and high specificity when compared to the control groups. Blood was shown to exhibit two to three times more vCJD than urine, so blood was chosen as the optimal medium for prion detection.

This noninvasive method to detect the presence of the vCJD biomarker brings us closer to tackling prion diseases. There is, however, still a long way to go in improving the PMCA detection method. Since the group only tested a small number of cases (14), an important next step is to expand the sample size to further test the effectiveness and viability of the method. Additionally, the blood samples were all obtained from patients who were in the later stages of the disease, so more preclinical stage studies will need to be performed to ensure the method can effectively find presymptomatic, early stage patients. It is therefore crucial that we conduct more studies to establish and fine-tune the possible usefulness of PMCA in presymptomatic prion disease detection. We should ultimately be able to pinpoint the earliest stage of the disease where PMCA can detect PrPSc in blood. Overall however the PMCA technology in detecting the PrPSc prion in mad cow disease seems to be a promising lead in our quest for early disease detection. Achieving that would be very significant since diagnosis in the early stages of the disease will open up new possibilities for treatment of these prion disorders.

Image source: http://www.nature.com/polopoly_fs/7.2541.1327594108!/image/1.9904.jpg_gen/derivatives/landscape_300/1.9904.jpg

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